ALTERATIONS IN PULMONARY BLOOD FLOW IN THE LAMB INDUCES CHANGES IN PULMONARY VASCULAR MORPHOLOGY AND GROWTH FACTOR EXPRESSION. • 121

Abstract

Congenital heart defects are associated with structural abnormalities of the pulmonary circulation, which depend on the amount of pulmonary blood flow. With increased blood flow, there is increased pulmonary artery size, medial smooth muscle hypertrophy, and extension of this muscle into nonmuscular pulmonary arteries. With decreased blood flow, there is decreased number and size of pulmonary arteries, and decreased muscularity. We have developed models of increased (insertion of an aortopulmonary vascular graft) and decreased (unilateral pulmonary artery banding) pulmonary blood flow in fetal lambs. By 4 weeks of age, these lambs demonstrate structural abnormalities of the pulmonary circulation. The cellular and molecular mechanisms underlying these changes are not understood. Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have effects on the proliferation of endothelial and vascular smooth muscle cells, and on the formation of new capillaries and larger vessels. To evaluate the role of these growth factors in controlling pulmonary vascular growth, we cloned ovine bFGF and VEGF cDNA fragments. Lung tissues were obtained from 4-week-old lambs with normal, increased or decreased pulmonary blood flow. RNase protection assays,in situ hybridization, and Western blot analyses (using commercial antibodies) were performed. Increased pulmonary blood flow, with resulting increased size and number of pulmonary arteries, is associated with increased gene and protein expression for bFGF (3-fold) and VEGF (5-fold); while decreased pulmonary blood flow, with resulting decreased size and number of pulmonary arteries, is associated with decreased gene and protein expression for bFGF (2-fold) and VEGF (2-fold). A better understanding of the cellular and molecular mechanisms controlling pulmonary vascular growth may lead to new treatment strategies for children with congenital heart defects.